Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1)

…, C Condra, J Karczewski, RA Bednar, SL Gaul…

Index: Nantermet, Philippe G; Barrow, James C.; Lundell, George F.; Pellicore, Janetta M.; Rittle, Kenneth E.; Young, MaryBeth; Freidinger, Roger M.; Connolly, Thomas M.; Condra, Cindra; Karczewski, Jerzy; Bednar, Rodney A.; Gaul, Stanley L.; Gould, Robert J.; Prendergast, Kris; Selnick, Harold G. Bioorganic and Medicinal Chemistry Letters, 2002 , vol. 12, # 3 p. 319 - 323

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Citation Number: 46

Abstract

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC50s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the ...